Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents
© 2020 Wiley-VCH GmbH..
Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC50 =78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
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| Enthalten in: |
ChemMedChem - 15(2020), 23 vom: 03. Dez., Seite 2280-2285 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jastaniah, Ammar [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.09.2021 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cmdc.202000385 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC50 =78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice | ||
| 650 | 4 | |a Journal Article | |
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